It is known that ketone bodies, particularly (R)-3-hydroxybutyrate (D-β-hydroxybutyrate) and acetoacetate, have both nutritional and therapeutic applications in man and many species of animals. U.S. Pat. No. 6,136,862 and U.S. Pat. No. 6,232,345 (incorporated herein by reference) relate to the use of D-β-hydroxybutyrate, oligomers, esters and salts thereof, inter alia, in the treatment of cerebral edema and cerebral infarction. U.S. Pat. No. 6,207,856 and PCT/US99/21015 also refer to β-hydroxybutyrate and its oligomers, esters and salts thereof in protecting against other forms of nearodegeneration inter alia, through their proposed ability to activate the tricarboxylic acid (TCA) cycle and, through favourable redox reactions in cells and antioxidant activity, scavenge free radicals. β-Hydroxybutyrate has also been demonstrated to have cardioprotectant effect and can increase cardiac efficiency (Sato et al, FASEB J, 9: 651-658, 1995).
It is also known, based on studies of the EEG power spectra measured in freely-moving rats, that D-β-hydroxybutyrate and the induction of ketosis have therapeutic utility in the treatment of conditions including, but not limited to, affective and related psychiatric disorders, which include depression, anxiety, schizo-affective disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder and post-traumatic stress disorder, impaired cognitive function and pain (Copending PCT/GB2005/01835); also in providing symptomatic relief in the treatment of Parkinson's Disease (PD) and other CNS disorders resulting from dopamine deficiency in the brain and also treating and preventing attention deficit hyperactivity disorder (ADHD) and related CNS disorders of cognition, impulsiveness, attention and aggression in children, adolescents and adults (Copending U.S. Provisional Applications 60/611301 and 60/611302).
U.S. Pat. No. 6,207,856, U.S. Pat. No. 6,136,862, U.S. Pat. No. 6,207,856 and PCT/US99/21015, incorporated herein by reference, teach that preferred ketogenic precursors for producing such ketosis are monohydric-, dihydric and trihydric alcoholic esters of (R)-3-hydroxybutyrate, but particularly a (R)-3-hydroxybutyryl ester of (R)-1,3-butandiol, more preferably the diester formed from two molecules of (R)-3-hydroxybutyrate and one molecule of (R)-1,3-butandiol.
However, it is also known that production of oligomers of (R)-3-hydroxybutyrate in pure form is problematic. PCT/US99/21015 exemplifies a ketogenic oligomer with a mixture of (R)-3-hydroxybutyrate trimer, tetramer and pentamer and exemplifies esters thereof with acetoacetyl trimer, tetramer and pentamer of (R)-3-hydroxybutyrate. Similarly, Hiraide et al (1999) J. Parenteral and Enteral Nutrition Vol 23. No 6 discloses the use of a mixture of dimer and trimer of (R)-3-hydroxybutyrate for studies performed to determine the ability of plasma to degrade these molecules to the monomer, (R)-3-hydroxybutyrate.
In order to ensure that previously untested material is safe and appropriate for human administration, by any route, it is first necessary to evaluate all of its significant components for toxicity and efficacy. In the case of multi-component materials, it is, therefore, necessary to evaluate each one of the components in a variety of toxicology and efficacy tests. Such tasks can be extremely expensive and time-consuming, and inevitably, this will be an important factor in any decision on whether or not to proceed with any particular assessment. Furthermore, a mixture of different components may need to be produced in a set ratio for its safety and efficacy evaluation to be valid.